cAMP exerts a profound effect on cellular differentiation, in part, by stimulating the transcription of specific genes. We have previously purified and characterized a nuclear phosphoprotein, CREB, which regulates cAMP responsive genes in mature cells by recognizing a conserved cAMP response element (CRE). Structure-function studies with the cloned cDNA reveal that CREB activity is regulated by cAMP-dependent protein kinase (PK-A) through phosphorylation at a single serine phosphoacceptor site. We now propose to test the hypothesis that, in developing cells, the cAMP Response Unit, consisting of CREB and PK-A, is additionally regulated through the selective induction of the CREB gene. Once established, the activity of CREB in differentiating cells is further dependent on retinoic acid inducible factor(s) which tightly regulate the ability of cells to respond to cAMP. The proposed studies will help to elucidate the mechanisms by which gene expression is coordinately regulated in the developing brain.